Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases

Justyna Jezierska, Giovanni Stevanin, Hiroyuki Watanabe, Michiel R. Fokkens, Fabien Zagnoli, Jerome Kok, Jean-Yves Goas, Pierre Bertrand, Christophe Robin, Alexis Brice, Georgy Bakalkin, Alexandra Durr, Dineke S. Verbeek*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

15 Citaten (Scopus)

Samenvatting

We have recently identified missense mutations in prodynorphin (PDYN), the precursor to dynorphin opioid peptides, as the cause for spinocerebellar ataxia (SCA23) in Dutch ataxia cases. We report a screen of PDYN for mutations in 371 cerebellar ataxia cases, which had a positive family history; most are of French origin. Sequencing revealed three novel putative missense mutations and one heterozygous two-base pair deletion in four independent SCA patients. These variants were absent in 400 matched controls and are located in the highly conserved dynorphin domain. To resolve the pathogenicity of the heterozygous variants, we assessed the peptide production of the mutant PDYN proteins. Two missense mutations raised dynorphin peptide levels, the two-base pair deletion terminated dynorphin synthesis, and one missense mutation did not affect PDYN processing. Given the outcome of our functional analysis, we may have identified at least two novel PDYN mutations in a French and a Moroccan SCA patient. Our data corroborates recent work that also showed that PDYN mutations only account for a small percentage (similar to 0.1 %) of European SCA cases.

Originele taal-2English
Pagina's (van-tot)1807-1812
Aantal pagina's6
TijdschriftJournal of Neurology
Volume260
Nummer van het tijdschrift7
DOI's
StatusPublished - jul-2013

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